Methods and compositions for treating chronic lung diseases

ABSTRACT

The present invention provides, among other things, methods and compositions for treating Chronic Lung Disease (CLD), comprising administering to a subject in need of treatment a composition comprising insulin-like growth factor-1 (IGF-1) or an agonist or an analog thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 62/557,113 filed Sep. 11, 2017, the disclosure of which is herebyincorporated by reference in its entirety.

BACKGROUND

Of an estimated 4.2 million live births in the United States each year,approximately 383,000 (about 9%) occur prematurely. Preterm labor andits complications are major perinatal public health issues in developedsocieties today. Low birth-weight infants or infants born prematurelymiss a major part of the critical period of in utero growth. Theyaccount for half of all infant deaths and three-quarters of long-termmorbidity. They impose a heavy burden on the national economy, becauseof the high costs of special care in both the neonatal period and overthe life-span of survivors. Many survivors also have diminished qualityof life because of physical damage resulting directly from prematurity.

The length of a normal pregnancy or gestation is considered to be 40weeks (280 days) from the date of conception. Infants born before 37weeks gestation are considered premature and may be at risk forcomplications. Advances in medical technology have made it possible forinfants born as young as 23 weeks gestational age (17 weeks premature)to survive. Infants born prematurely are at higher risk for death orserious complications due to their low birth weight and the immaturityof their body systems. Low birthweight, defined by a cut-off of 2,500 g,serves as a marker for high risk newborns, as it is correlated withprenatal risk factors, intrapartum complications and neonatal disease,and is composed largely of preterm births. Studies on very lowbirthweight, defined as less than 1,500 g or less than 1,000 g cut-offsthat identify infants at highest risk, those with high rates of severerespiratory and neurological complications associated with extremeprematurity. (See, Hack, M., Klein, N. K., & Taylor, H. G., Long-termdevelopmental outcomes of low birth weight infants. The Future ofChildren, 5,176-196 (1995)).

The lungs, digestive system, and nervous system (including the brain)are not fully developed in premature babies, and are particularlyvulnerable to complications. The most prevalent medical problemsencountered in preterm infants are retinopathy of prematurity,developmental delay, mental retardation, bronchopulmonary dysplasia(BPD), necrotizing enterocolitis, and intraventricular hemorrhage.

Chronic Lung Disease (CLD) is a particularly complicated and lifethreatening condition in premature infants. Premature infants,especially those extremely premature infants, are at very high risk fordeveloping chronic lung disease, with bronchopulmonary dysplasia (BPD)at term being an early manifestation. The long term trajectory ofpulmonary outcomes in infants born extremely premature commonly startswith antenatal risk factors, followed by respiratory distress syndrome(RDS) in the first hours or days of life requiring respiratory support,leading up to a diagnosis of BPD in those who survive to termequivalence, and finally chronic respiratory morbidity as they grow intoinfancy, early childhood and often even school age or adolescence thatresults in more frequent re-hospitalizations and ER visits forrespiratory causes, the need for respiratory medications or homerespiratory support, and many suffer from a form of reactive airwaydisease that continues to limit their quality of life. A largeproportion of infants with BPD at 36 weeks will develop persistent lungdisease at 12-24 months corrected age, but there are also infantswithout a diagnosis of BPD who develop Chronic Lung Disease later ininfancy.

SUMMARY

The present invention provides an effective treatment of Chronic LungDisease (CLD) in premature infants. The invention is, in part, based onthe insights that a combination of IGF-1 and insulin-like growth factorbinding protein-3 (IGFBP-3) can improve not only the short term outcomesbut also the longer term conditions related to chronic lung disease,resulting in significantly improved growth and development arch ofinfants born extremely premature starting immediately after birth whencut off from the maternal supply of IGF-1 and through its replacement.

In one aspect of the present disclosure, a method of treating ChronicLung Disease (CLD) is provided, comprising administering to a subject inneed of treatment, a composition comprising insulin-like growth factor-1(IGF-1) or an agonist or an analog thereof. In some embodiments, amethod of treating CLD is provided, comprising administering to asubject in need of the treatment, a composition comprising the IGF-I oragonist or analog thereof comprising IGF-1 and an IGF binding protein.In some embodiments, the composition comprises the IGF-I or agonist oranalog thereof and also comprises IGF-1 and insulin-like growth factorbinding protein-3 (IGFBP-3).

In some embodiments, the subject in need of the treatment is an infant.In some embodiments, the subject is a premature infant, wherein theinfant is prematurely born by at least 1 week, 2 weeks, 3 weeks, 4weeks, 5 weeks, 6 weeks, 7 weeks, 2 months, 10 weeks or 3 months.

In some embodiments, the subject in need of the treatment isadministered a composition comprising the IGF-I or agonist or analog,wherein the composition is administered subcutaneously, intravenously,intramuscularly, or orally. In some embodiments, the IGF-I or agonist oranalog thereof is administered intravenously. In some embodiments, theIGF-I or agonist or analog thereof is administered at a dosage of about100 to 500 micrograms/kg/24 hours. In some embodiments, the IGF-I oragonist or analog thereof is administered at a dosage of between 100micrograms/kg/24 hours and 450 micrograms/kg/24 hours. In someembodiments, the IGF-I or agonist or analog thereof is administered at adosage of between 150 micrograms/kg/24 hours and 400 micrograms/kg/24hours. In some embodiments, the IGF-I or agonist or analog thereof isadministered at a dosage of between 200 micrograms/kg/24 hours and 400micrograms/kg/24 hours. In some embodiments, the IGF-I or agonist oranalog thereof is administered at a dosage of between 250micrograms/kg/24 hours and 400 micrograms/kg/24 hours. In someembodiments, the IGF-I or agonist or analog thereof is administered at adosage of about 250 micrograms/kg/24 hours. In some embodiments, theIGF-I or agonist or analog thereof is administered at a dosage of about400 micrograms/kg/24 hours. In some embodiments, the IGF-I or agonist oranalog thereof is administered from the time of birth up topost-menstrual age (PMA) of about 24-34 weeks. PMA is defined as the agein weeks of an infant in weeks when he or she is discharged fromhospital, or the age of death, or first birthday, whichever comes first.It is calculated as the sum of (i) the product of total gestation weeksand seven, (ii) the number of gestation days, and (iii) the days oflength of stay in the hospital after birth. In some embodiments, theIGF-I or agonist or analog thereof is administered from the time ofbirth up to PMA of about 28 to 32 weeks. In some embodiments, the IGF-Ior agonist or analog thereof is administered from the time of birth upto PMA of about 29 weeks plus 6 days.

In some embodiments of the disclosure, the subject has reduced IGF-1serum levels. In some embodiments, the reduced IGF-1 serum levels arebelow 60 micrograms/L. In some embodiments, the reduced IGF-1 serumlevels are below 50 micrograms/L. In some embodiments, the reduced IGF-1serum levels are below 40 micrograms/L. In some embodiments, the reducedIGF-1 serum levels are about 30 to 50 micrograms/L.

In some embodiments, the IGF-1 is recombinantly produced. In someembodiments, the IGFBP-3 is recombinantly produced. In some embodiments,the IGF-1 and the IGFBP-3 are complexed prior to administration to thesubject. In some embodiments, the IGF-1 and IGFBP-3 are complexed inequimolar amounts.

The method provided herein comprises embodiments where theadministration of the IGF-I or agonist or analog results in reducedincidence of Chronic Respiratory Morbidity (CRM) through 12 monthscorrected age (CA). The corrected age of an infant is the adjusted ageof the infant based on his or her due date. Taking the term of thepregnancy to be 40 weeks (i.e., due date), a prematurely born infantgets a corrected age where the excess time it has existed outside themother's body is subtracted from its real age. In some embodiments, theadministration of the IGF-I or agonist or analog results in reducedincidence of Bronchopulmonary Dysplasia (BPD) through postmenstrual age(PMA) 24 weeks to 12 months. For example, the administration of theIGF-I or agonist or analog results in reduced incidence of BPD throughPMA 24 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, or 38,or 40 weeks, 45 weeks, 50 weeks, or 52 weeks. In some other embodiments,the administration of the IGF-I or agonist or analog results in reducedincidence of BPD through PMA 6 months, 8 months, 10 months, or 12months. In some embodiments, the administration of the IGF-I or agonistor analog thereof results in reduced incidence of SevereIntraventricular Hemorrhage (IVH) Grade III or IV through postmenstrualage (PMA) 24 weeks, 30 weeks, 36 weeks, 40 weeks, 6 months, 8 months, 10months, or 12 months. In some embodiments, the administration of theIGF-I or agonist or analog thereof results in reduced incidence ofretinopathy of prematurity (ROP) through postmenstrual age (PMA) 24weeks, 30 weeks, 36 weeks, 40 weeks, 6 months, 8 months, 10 months, or12 months.

The method disclosed herein comprises embodiments where theadministration of the IGF-I or agonist or analog results in increasedFunctional Status as Assessed by PREMature Infant Index (PREMII) throughpostmenstrual age (PMA) 24 weeks, 30 weeks, 32 weeks, 34 weeks, 36weeks, 38 weeks, 40 weeks, 50 weeks, 6 months, 8 months, 10 months, or12 months.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof that theforegoing description as well as the examples that follow are intendedto illustrate and not limit the scope of the invention. Other aspects,advantages and modifications within the scope of the invention will beapparent to those skilled in the art to which the invention pertains.

DETAILED DESCRIPTION

The present invention provides methods and compositions for treatingChronic Lung Disease. The compositions and methods provided herein areparticularly effective in treating Chronic Lung Disease in prematureinfants, especially those extremely premature infants. In someembodiments, a method of the invention involves administering to asubject in need of treatment (e.g., a premature infant) insulin-likegrowth factor-1 (IGF-1) or an agonist or an analog thereof. In someembodiments, the IGF-I or agonist or analog thereof contains IGF-1 andan IGF binding protein (e.g., insulin-like growth factor bindingprotein-3 (IGFBP-3)).

Various aspects of the invention are described in detail in thefollowing sections. The use of sections is not meant to limit theinvention. Each section can apply to any aspect of the invention. Inthis application, the use of “or” means “and/or” unless statedotherwise.

Definitions

“Preterm” or “preterm birth” or “prematurity” or “premature infant” or“premature baby”, or grammatical equivalents, refers to birth of apatient prior to 40 weeks of gestation or weighing 10% less than theaverage for the patient's gestational age. In some embodiments, apremature infant refers to an infant that was prematurely born by atleast 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, or 3 months.“IGF-I” refers to insulin-like growth factor I from any species,including bovine, ovine, porcine, equine, and human, preferably human,and, if referring to exogenous administration, from any source, whethernatural, synthetic, or recombinant, provided that it will bind IGFbinding protein at the appropriate site. IGF-I can be producedrecombinantly, for example, as described in PCT publication WO 95/04076.

An “IGFBP” or an “IGF binding protein” refers to a protein orpolypeptide from the insulin-like growth factor binding protein familyand normally associated with or bound or complexed to IGF-I whether ornot it is circulatory (i.e., in serum or tissue). Such binding proteinsdo not include receptors. This definition includes IGFBP-1, IGFBP-2,IGFBP-3, IGFBP-4, IGFBP-5, IGFBP-6, Mac 25 (IGFBP-7), andprostacyclin-stimulating factor (PSF) or endothelial cell-specificmolecule (ESM-1), as well as other proteins with high homology toIGFBPs. Mac 25 is described, for example, in Swisshelm et al., Proc.Natl. Acad. Sci. USA, 92: 4472-4476 (1995) and Oh et al., J. Biol.Chem., 271: 30322-30325 (1996). PSF is described in Yamauchi et al.,Biochemical Journal, 303: 591-598 (1994). ESM-1 is described in Lassalleet al., J. Biol. Chem., 271: 20458-20464 (1996). For other identifiedIGFBPs, see, e.g., EP 375,438 published Jun. 27, 1990; EP 369,943published May 23, 1990; WO 89/09268 published Oct. 5, 1989; Wood et al.,Molecular Endocrinology, 2: 1176-1185 (1988); Brinkman et al., The EMBOJ., 7: 2417-2423 (1988); Lee et al., Mol. Endocrinol., 2: 404-411(1988); Brewer et al., BBRC, 152: 1289-1297 (1988); EP 294,021 publishedDec. 7, 1988; Baxter et al., BBRC, 147: 408-415 (1987); Leung et al.,Nature, 330: 537-543 (1987); Martin et al., J. Biol. Chem., 261:8754-8760 (1986); Baxter et al., Comp. Biochem. Physiol., 91B: 229-235(1988); WO 89/08667 published Sep. 21, 1989; WO 89/09792 published Oct.19, 1989; and Binkert et al., EMBO J., 8: 2497-2502 (1989).

“IGFBP-3” refers to insulin-like growth factor binding protein 3.IGFBP-3 is a member of the insulin-like growth factor binding proteinfamily. IGFBP-3 may be from any species, including bovine, ovine,porcine and human, in native-sequence or variant form, including but notlimited to naturally-occurring allelic variants. IGFBP-3 may be from anysource, whether natural, synthetic or recombinant, provided that it willbind IGF-I at the appropriate sites. IGFBP-3 can be producedrecombinantly, as described in PCT publication WO 95/04076.

A “therapeutic composition,” as used herein, is defined as comprisingIGF-I, an analog thereof, or IGF-I in combination with its bindingprotein, IGFBP-3 (IGF-I/IGFBP-3 complex). The therapeutic compositionmay also contain other substances such as water, minerals, carriers suchas proteins, and other excipients known to one skilled in the art.

“Analogs” of IGF-I are compounds having the same therapeutic effect asIGF-I in humans or animals. These can be naturally occurring analogs ofIGF-I (e.g., truncated IGF-I) or any of the known synthetic analogs ofIGF-I. See, for example, U.S. Pat. No. 5,473,054 for analog compounds ofIGF-I.

“Agonists” of IGF-I are compounds, including peptides, which are capableof increasing serum and tissue levels of IGF, especially IGF-I, in amammal and particularly in a human. See, for example, U.S. Pat. No.6,251,865 for IGF agonist molecules.

“Developmental delay” as used herein shall mean abnormal neurogenesiswhich has the potential of leading to slowed mental progression inachieving developmental milestones. Developmental delay can, in somecases, be determined by means of electroencephalogram.

“Subject” as used herein means any mammal, including humans. In certainembodiments of the present invention the subject is an adult, anadolescent or an infant. Also contemplated by the present invention arethe administration of the pharmaceutical compositions and/or performanceof the methods of treatment in-utero.

As used herein, the term “treatment” (also “treat” or “treating”) refersto any administration of a therapeutic composition (e.g., IGF-1 or anagonist or an analog thereof) that partially or completely alleviates,ameliorates, relieves, inhibits, delays onset of, prevents, reducesseverity of and/or reduces incidence of one or more symptoms or featuresof a particular disease, disorder, and/or condition (e.g., Chronic lungdisease). Such treatment may be of a subject who does not exhibit signsof the relevant disease, disorder and/or condition and/or of a subjectwho exhibits only early signs of the disease, disorder, and/orcondition. Alternatively or additionally, such treatment may be of asubject who exhibits one or more established signs of the relevantdisease, disorder and/or condition.

As used herein, the terms “improve,” “increase” or “reduce,” orgrammatical equivalents, indicate values that are relative to a baselinemeasurement, such as a measurement in the same individual prior toinitiation of the treatment described herein, or a measurement in acontrol individual (or multiple control individuals) in the absence ofthe treatment described herein, or historical reference or data. A“control individual” is an individual afflicted with the same form ofChronic Lung Disease as the individual being treated, who is about thesame age as the individual being treated (to ensure that the stages ofthe disease in the treated individual and the control individual(s) arecomparable).

Chronic Lung Disease

The present invention may be used to treat any type of Chronic LungDisease (CLD) including CLD that occurs in the adult especially theelderly and infants especially those premature or extremely prematureinfants. CLD involves a spectrum of diseases and disorders, includingbut not limited to COPD (emphysema and chronic bronchitis), asthma,cystic fibrosis, restrictive lung disease, and persistent infections.

-   -   Chronic Lung Disease of Prematurity

Extremely premature infants are at very high risk for developing chroniclung disease. Premature babies may need a breathing machine (ventilator)and extra oxygen to breathe. Chronic Lung Disease happens when abreathing machine or oxygen injures a premature baby's lungs. With alung injury, the tissues inside a baby's lungs get inflamed. The tissuecan break down, causing scarring. The scarring can cause troublebreathing, and the baby may need more oxygen. Lung injury may be causedby:

-   -   Prematurity: A premature baby's lungs aren't fully formed. This        is especially true of the air sacs.    -   Low amounts of surfactant: This is a substance in the lungs that        helps keep the tiny air sacs open.    -   Oxygen use: High amounts of oxygen can harm the cells in the        lungs.    -   Breathing machine (mechanical ventilation): Air pressure can        harm the lungs. This pressure may come from breathing machines,        suctioning of the airways, and use of an endotracheal (ET) tube.        An ET tube is a tube placed in your baby's windpipe (trachea)        and connected to a breathing machine.

The long term trajectory of pulmonary outcomes in infants born extremelypremature commonly starts with antenatal risk factors, followed byrespiratory distress syndrome (RDS) in the first hours or days of liferequiring respiratory support, leading up to a diagnosis of BPD in thosewho survive to term equivalence, and finally chronic respiratorymorbidity as they grow into infancy, early childhood and often evenschool age or adolescence that results in more frequentre-hospitalizations and ER visits for respiratory causes, the need forrespiratory medication or home respiratory support, and many suffer froma form of reactive airway disease that continues to limit their qualityof life.

IGF-1 or an Agonist or an Analog Thereof

IGF-1 or an agonist or an analog thereof may be used to practice thepresent invention. IGF-I is a well-known regulator of postnatal growthand metabolism. See, Baker J, Liu J P, Robertson E J, Efstratiadis A. Ithas a molecular weight of approximately 7.5 kilodaltons (Kd). Mostcirculating IGF is bound to the IGF-binding protein, and moreparticularly to the IGFBP-3. IGF-I may be measured in blood serum todiagnose abnormal growth-related conditions.

Typically, a therapeutic composition suitable for treatment of CLDaccording to the present invention contains an IGF-1 and an IGF-1binding protein such as IGF binding-proteins (IGFBPs). At least sixdistinct IGF binding-proteins (IGFBPs) have been identified in varioustissues and body fluids. In some embodiments, a suitable therapeuticcomposition according to the present invention contains IGF-1 andIGFBP-3. IGF-1 and IGFBP-3 may be used as a protein complex orseparately.

IGF-I and IGF-I binding proteins such as IGFBP-3 may be purified fromnatural sources or produced by recombinant means. For instance,purification of IGF-I from human serum is well known in the art(Rinderknecht et al. (1976) Proc. Natl. Acad. Sci. USA 73:2365-2369).Production of IGF-I by recombinant processes is shown in EP 0128733,published in December of 1984. IGFBP-3 may be purified from naturalsources using a process such as that shown by Baxter et al. (1986,Biochem. Biophys. Res. Comm. 139:1256-1261). Alternatively, IGFBP-3 maybe synthesized recombinantly as discussed by Sommer et al., pp. 715-728,Modern Concepts Of Insulin-Like Growth Factors (E. M. Spencer, ed.,Elsevier, N.Y., 1991). Recombinant IGFBP-3 binds IGF-I in a 1:1 molarratio.

Pharmaceutical Composition and Therapeutic Use

The present invention provides compositions and methods for treating apatient suffering from a Chronic Lung Disease (CLD), in particular, CLDassociated with prematurity. For example, the present invention may beused to treat a premature infant who is suffering from CLD orcomplication associated with CLD. In some embodiments, the presentinvention may be used to treat infant who is prematurely born by atleast 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, or 3 months.In some embodiments, the present invention may be used to treatextremely premature infant.

In one embodiment of the invention, IGF-I or an analog thereof isadministered in combination with IGF binding protein capable of bindingIGF-I. In some embodiment, the IGF binding protein capable of bindingIGF-I is IGF binding protein 3 (IGFBP-3).

A composition comprising equimolar amounts of IGF-I and IGF-bindingprotein may be used. In some embodiments, the IGF-I and IGF bindingprotein are complexed prior to administration. The complex may be formedby mixing approximately equimolar amounts of IGF-I and IGF bindingprotein dissolved in physiologically compatible carriers such as normalsaline, or phosphate buffered saline solution. In some embodiments, aconcentrated solution of recombinant human IGF-I and a concentratedsolution of recombinant human IGF binding protein are mixed together fora sufficient time to form an equimolar complex. In some embodiments,recombinant human IGF-I and recombinant human IGF binding protein arecombined to form a complex during purification as described inInternational Patent Application No. WO 96/40736.

For therapeutic applications, IGF-I or an analog thereof may be suitablyadministered to a patient, alone or as part of a pharmaceuticalcomposition, comprising the IGF-I or an analog thereof together with oneor more acceptable carriers thereof and optionally other therapeuticingredients. The carrier(s) must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The pharmaceutical compositions of the invention include those suitablefor oral, nasal, topical (including buccal and sublingual), orparenteral (including subcutaneous, intramuscular, intravenous andintradermal) administration. The formulations may conveniently bepresented in unit dosage form, e.g., tablets and sustained releasecapsules, and in liposomes, and may be prepared by any methods wellknown in the art of pharmacy. See, for example, Remington'sPharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa.(17th ed. 1985).

Such preparative methods include the step of bringing into associationwith the molecule to be administered ingredients such as the carrierwhich constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers or both, and then if necessary shaping theproduct.

Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion, or packed in liposomes and as a bolus,etc.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, preservative, surface-active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets optionally may be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tablets.

The inventive methods disclosed herein provide for the parenteral anoral administration of IGF-I, an analog or an agonist thereof, or IGF-Ior an analog in combination with IGF binding protein complex to infantsin need of such treatment. Parenteral administration includes, but isnot limited to, intravenous (IV), intramuscular (IM), subcutaneous (SC),intraperitoneal (IP), intranasal, and inhalant routes. In the method ofthe present invention, IGF-I, an agonist or an analog thereof arepreferably administered orally. IV, IM, SC, and IP administration may beby bolus or infusion, and may also be by slow release implantabledevice, including, but not limited to pumps, slow release formulations,and mechanical devices. The formulation, route and method ofadministration, and dosage will depend on the disorder to be treated andthe medical history of the patient. In some embodiments, the IGF-I oragonist or analog thereof is administered intravenously.

A pharmaceutical composition according to the present invention may beadministered at various doses. For example, a suitable dosage may rangefrom about 100 to 500 micrograms/kg/24 hours. In some embodiments, asuitable dosage may be or greater than about 100 micrograms/kg/24 hours,150 micrograms/kg/24 hours, 200 micrograms/kg/24 hours, 250micrograms/kg/24 hours, 300 micrograms/kg/24 hours, 350 micrograms/kg/24hours, 400 micrograms/kg/24 hours, 450 micrograms/kg/24 hours, or 500micrograms/kg/24 hours. In some embodiments, a pharmaceuticalcomposition according to the invention is administered from the time ofbirth up to post-menstrual age (PMA) of about 24-34 weeks, up to PMA ofabout 28 to 32 weeks, up to PMA of about 29 weeks plus 6 days.

The method provided herein comprises embodiments where theadministration of the IGF-I or agonist or analog results in reducedincidence of Chronic Respiratory Morbidity (CRM) through 12 monthscorrected age (CA). In some embodiments, the administration of the IGF-Ior agonist or analog results in reduced incidence of Bronchopulmonarydysplasia (BPD) through postmenstrual age (PMA) 36 weeks, 40 weeks, 6months, 8 months, 10 months, or 12 months. In some embodiments, theadministration of the IGF-I or agonist or analog thereof results inreduced incidence of Severe Intraventricular Hemorrhage (IVH) Grade IIIor IV through postmenstrual age (PMA) 36 weeks, 40 weeks, 6 months, 8months, 10 months, or 12 months. In some embodiments, the administrationof the IGF-I or agonist or analog thereof results in reduced incidenceof retinopathy of prematurity (ROP) through postmenstrual age (PMA) 36weeks, 40 weeks, 6 months, 8 months, 10 months, or 12 months.

The method disclosed herein comprises embodiments where theadministration of the IGF-I or agonist or analog results in increasedFunctional Status as Assessed by PREMature Infant Index (PREMII) throughpostmenstrual age (PMA) 36 weeks, 40 weeks, 6 months, 8 months, 10months, or 12 months.

For parenteral or oral administration, compositions of the complex maybe semi-solid or liquid preparations, such as liquids, suspensions, andthe like. Physiologically compatible carriers are those that arenon-toxic to recipients at the dosages and concentrations employed andare compatible with other ingredients of the formulation. For example,the formulation preferably does not include oxidizing agents and othercompounds that are known to be deleterious to polypeptides. Hence,physiologically compatible carriers include, but are not limited to,normal saline, serum albumin, 5% dextrose, plasma preparations, andother protein-containing solutions. Optionally, the carrier may alsoinclude detergents or surfactants.

In yet another aspect of the invention there is provided use of anIGF-I, an agonist or analog thereof in the manufacture of a therapeuticcomposition for treating a complication of preterm birth.

Finally, there is also provided an article of manufacture comprisingpackaging material and a pharmaceutical agent contained within thepackaging material. The packaging material comprises a label whichindicates that the pharmaceutical may be administered, for a sufficientterm at an effective dose, for treating and/or preventing complicationsassociated with preterm birth. The pharmaceutical agent comprises IGF-I,an agonist or an analog thereof together with a pharmaceuticallyacceptable carrier.

The invention will be further characterized by the following exampleswhich are intended to be exemplary of the invention.

EXAMPLES Example 1 Treatment of CLD in Extremely Premature Infants

An investigational drug comprising insulin like growth factor-1/insulin-like growth factor binding protein-3 (rhIGF-1/rhIGFBP-3)complex was studied for therapeutic effect in CLD. It is designed as amulticenter, randomized, open-label, controlled, 3-arm study to evaluatethe clinical efficacy and safety of the therapeutic composition inpreventing human chronic lung disease. This study is undertaken onsubjects through 12 months corrected age (CA) compared to standardneonatal care in extremely premature infants. The study is reviewed andapproved by the institutional review board (IRB)/independent ethicscommittee (IEC) of the responsible institution.

Purpose: The purpose of this study is to determine if an investigationaldrug comprising rhIGF-1/rhIGFBP-3 (henceforth, the therapeuticcomposition) can reduce respiratory complications in extremely prematurebabies through 12 months corrected age (CA), as compared to extremelypremature babies receiving standard neonatal care alone.

Study Subjects: The subjects are between gestational age (GA) of 23weeks+0 days and 27 weeks+6 days. Subjects include both sexes. At leastfifty subjects are included in the study.

Exclusion criteria: The exclusion criteria include detectable grossmalformation, known or suspected chromosomal abnormality, geneticdisorder or syndrome, according to the investigator's opinion. Theexclusion criteria also include persistent blood glucose level less than(<) 2.5 millimoles per liter (mmols/L) at the baseline visit to excludesevere congenital abnormalities of glucose metabolism; clinicallysignificant neurological disease according to the investigator'sopinion; monozygotic multiples; and any other condition that may poserisk to the subject or interfere with the subject's ability to becompliant with the protocol or interfere with the interpretation ofresults. If the subject is participating or plans to participate in aclinical study of another investigational study drug, device, orprocedure (participation in observational studies is permitted on acase-by-case basis) are excluded. If the subject or subject's parent orlegally authorized representative(s) is unable to comply with theprotocol or is unlikely to be available for long-term follow-up asdetermined by the investigator, the subject is also excluded.

Details of the Study Design: The primary purpose of the study isprevention of Bronchopulmonary Dysplasia and Chronic Lung Disease. It isan open label study, and the intervention model will be ParallelAssignment. The conditions monitored will be BPD and CLD.

250 Micrograms/Kg/24 hours of the therapeutic composition isadministered to one group of participants (Group A) by intravenousadministration (IV) from birth up to postmenstrual age (PMA) 29 weeks+6days. To another group of participants (Groups B), 400 micrograms/Kg/24hours of the therapeutic composition is administered by intravenousadministration (IV) from birth up to postmenstrual age (PMA) 29 weeks+6days. To the third group (Group C or control group), standard neonatalcare alone is provided.

The primary outcomes measured is incidence of Chronic RespiratoryMorbidity (CRM) Through 12 Months Corrected Age (CA) [Time Frame:Baseline through 12 Months Corrected Age (CA)] CRM is a common adverseoutcome of premature birth resulting in recurrent respiratory symptomsrequiring treatment with pulmonary medications such as bronchodilators,need for supplementary home oxygen, frequent emergency room visits orhospital readmissions, especially during the first year of life. CRMwill be measured by respiratory health care utilization and respiratorysymptoms.

The secondary outcomes include incidence of Bronchopulmonary Dysplasia(BPD) at Postmenstrual Age (PMA) 36 Weeks [Time Frame: PMA Week 36]. BPDis a chronic lung disorder characterized by pulmonary immaturity,undifferentiated alveoli with the presence of hyaline membrane andatelectasis, dilated capillaries immersed in the mesenchyme, and adistorted deposition of the extracellular matrix. BPD results inresidual effects on pulmonary function and is linked toneurodevelopmental problems during later childhood.

The secondary outcomes also include

-   -   Incidence of Severe Intraventricular Hemorrhage (IVH) Grade III        or IV Through Postmenstrual Age (PMA) 40 Weeks [Time Frame:        Baseline Through PMA 40 Weeks]    -   Incidence of Bronchopulmonary Dysplasia (BPD) at Postmenstrual        Age (PMA) 40 Weeks [Time Frame: PMA Week 40]    -   Incidence of Chronic Respiratory Morbidity (CRM) or Death        Through 6 Months Corrected Age (CA) [Time Frame: Baseline        through 6 Months Corrected Age (CA)] CRM is a common adverse        outcome of premature birth resulting in recurrent respiratory        symptoms requiring treatment with pulmonary medications such as        bronchodilators, need for supplementary home oxygen, frequent        emergency room visits or hospital readmissions, especially        during the first year of life. CRM will be measured by        respiratory health care utilization and respiratory symptoms.    -   Functional Status as Assessed by PREMature Infant Index (PREMII)        at Postmenstrual Age (PMA) 40 Weeks [Time Frame: PMA Week 36]        PREMII is a Clinician-Reported Outcome (ClinRO) assessment used        to capture overall functional maturation of extremely preterm        neonates. Functional Status is defined as what the infant can do        with respect to 8 key functional areas (feeding, weight gain,        thermoregulation, respiratory support, apnea, bradycardia,        desaturation events, and oxygen administration), as a reflection        of the infant's overall health and development.

Example 2 BPD Prevention in Extremely Premature Infants

A randomized study for effect of IGF-1/IGFBP3 in BPD prevention wasundertaken with an intervention model of parallel assignment. The studywas conducted in multiple centers in Italy, the Netherlands, Poland,Sweden, the United Kingdom and the United States between 18 Jun 2010 and30 Mar. 2016.

The drug Mecasermin Rinfabate, that is IGF-1/IGFBP3, was administered ascontinuous intravenous infusion in subjects from Study Day 0 (day ofbirth) up to and including PMA 29 weeks+6 days, when the subject'sendogenous production of IGF-1 is considered sufficient to maintainphysiologic serum IGF-1 levels. After discontinuation of study druginfusion, each subject will be followed to PMA 40 weeks±4 days. Thestudy was intended to determine the rhIGF-1/rhIGFBP-3 Dose, Administeredas a Continuous Infusion (CI), required to establish and maintainlongitudinal serum IGF-1 levels within physiological levels in prematureinfants, to prevent retinopathy of prematurity. This was a Phase 2,Randomized Controlled, Assessor-blind, dose confirming, pharmacokinetic,safety and efficacy of rhIGF-1/rhIGFBP-3. 61 Participants receivedinsulin-like growth factor (rhIGF-I)/insulin-like growth factor bindingprotein-3 (rhIGFBP-3) 250 microgram per kilogram (mcg/kg) for 24 hoursthrough continuous intravenous (IV) infusion from Day 0 up to 29 weeks 6days of post-menstrual age (PMA). As a control group, 60 participantsreceived standard of care alone. Table 1 illustrates the participantflow of the overall study

TABLE 1 Participant Flow: Overall Study Standard rhIGF-1/ of CarerhIGFBP-3 (Control) STARTED 61 60 COMPLETED 46 46 NOT COMPLETED 15 14Withdrawal by Subject 2 1 Adverse Event 11 9 Protocol Deviation 2 2Administrative Decision 0 1 Other Unspecified 0 1

TABLE 2 illustrates the population in the study. Standard rhIGF-1/ ofCare rhIGFBP-3 (Control) Total Overall Participants Analyzed 61 60 121[Units: Participants] Age 25.60 25.62 25.61 [Units: Weeks] (1.207)(1.397) (1.300) Mean (Standard Deviation) Sex: Female, Male [Units:Participants] Count of Participants Female 22 36.1% 21 35.0% 43 35.5%Male 39 63.9% 39 65.0% 78 64.5%

The secondary outcomes in a continuation of the study included amongother parameters:

-   -   Time to Discharge From Neonatal Intensive Care (TDNIC) [ Time        Frame: Day 0 to 40 Weeks Post Menstrual Age (EOS)]    -   Number of Participants With Bronchopulmonary Dysplasia (BPD)        [Time Frame: At 36 Weeks Post Menstrual Age]    -   Severity of BPD as mild, moderate and severe were based on the        National Institute of Child Health and Human Development (NICHD)        guidelines for preterm infants born at gestational age (GA) less        than (<) 32 weeks.    -   Mild: oxygen requirement during the first 28 days but in room        air at PMA 36 weeks or discharge to home, whichever comes first.    -   Moderate BPD: oxygen requirement during the first 28 days and        oxygen<30 percent (%) at PMA 36 weeks or discharge to home,        whichever comes first.    -   Severe BPD: oxygen requirement during the first 28 days and        oxygen greater than equal (≥) 30% through head hood or nasal        canula, or continuous positive airway pressure, or mechanical        ventilation, or high flow nasal cannula≥2 L/min at PMA 36 weeks        or discharge to home, whichever comes first.    -   Rate of Change in Body Weight [Time Frame: Day 0 to 40 Weeks        Post Menstrual Age (EOS)] The rate of change is the rate of        specific body weight change per day in kilogram (kg).    -   Rate of Change in Length [Time Frame: Day 0 to 40 Weeks Post        Menstrual Age (EOS)]    -   The rate of change is the length change per day in centimeter        (cm). Number of Participants With Treatment Emergent Adverse        Event (TEAE) and Treatment Emergent Serious Adverse Event        (TESAE) [Time Frame: Day 0 to 40 Weeks Post Menstrual Age (EOS)]    -   An adverse event (AE) was any untoward medical occurrence in a        participant who received study drug without regard to        possibility of causal relationship. A serious adverse event        (SAE) was an AE resulting in any of the following outcomes or        deemed significant for any other reason: death; initial or        prolonged in-patient hospitalization; life-threatening        experience (immediate risk of dying); persistent or significant        disability/incapacity; congenital anomaly.    -   Treatment-emergent adverse event was defined as the onset of any        AE or if the severity of a pre-existing AE worsened any time on        or after the date of first dose of investigational product.    -   Percentage of Serum IGF-1 Concentrations Falling Within Target        Range After Infusion of rhIGF-1/rhIGFBP-3 [Time Frame: Day 0 to        40 Weeks Post Menstrual Age (EOS)]    -   Serum samples were collected from treated and control        participants for quantitation of IGF-1 using validated        immunoassays. Target range of serum IGF-1 was 28-109 mcg/L. The        percentage of serum IGF-1 levels across treated participants        that fall within the range was reported.    -   Serum Concentrations of IGFBP-3 After Intravenous (IV) Infusion        of rhIGF-1/rhIGFBP-3 [Time Frame: Day 0 and Week 40 Post        Menstrual Age]    -   Serum Concentrations of Acid Labile Sub-unit (ALS) After        Intravenous (IV) Infusion of rhIGF-1/rhIGFBP-3 [Time Frame: Day        7 and Week 40 Post Menstrual Age]

TABLE 3 illustrates the measured values of BPD as secondary outcome.Standard rhIGF-1/ of Care rhIGFBP-3 (Control) Participants Analyzed 4749 [Units: Participants] Number of Participants With BronchopulmonaryDysplasia (BPD) [Units: Participants] No BPD 4 4 Mild 23 16 Moderate 9 5Severe 10 22 Unable to determine 1 2 No statistical analysis providedfor Number of Participants With Bronchopulmonary Dysplasia (BPD).

While certain compounds, compositions and methods described herein havebeen described with specificity in accordance with certain embodiments,the following examples serve only to illustrate the compounds of theinvention and are not intended to limit the same.

The articles “a” and “an” as used herein in the specification and in theclaims, unless clearly indicated to the contrary, should be understoodto include the plural referents. Claims or descriptions that include“or” between one or more members of a group are considered satisfied ifone, more than one, or all of the group members are present in, employedin, or otherwise relevant to a given product or process unless indicatedto the contrary or otherwise evident from the context. The inventionincludes embodiments in which exactly one member of the group is presentin, employed in, or otherwise relevant to a given product or process.The invention also includes embodiments in which more than one, or theentire group members are present in, employed in, or otherwise relevantto a given product or process. Furthermore, it is to be understood thatthe invention encompasses all variations, combinations, and permutationsin which one or more limitations, elements, clauses, descriptive terms,etc., from one or more of the listed claims is introduced into anotherclaim dependent on the same base claim (or, as relevant, any otherclaim) unless otherwise indicated or unless it would be evident to oneof ordinary skill in the art that a contradiction or inconsistency wouldarise. Where elements are presented as lists, (e.g., in Markush group orsimilar format) it is to be understood that each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should be understood that, in general, where the invention, oraspects of the invention, is/are referred to as comprising particularelements, features, etc., certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements, features, etc. For purposes of simplicity those embodimentshave not in every case been specifically set forth in so many wordsherein. It should also be understood that any embodiment or aspect ofthe invention can be explicitly excluded from the claims, regardless ofwhether the specific exclusion is recited in the specification. Thepublications, websites and other reference materials referenced hereinto describe the background of the invention and to provide additionaldetail regarding its practice are hereby incorporated by reference.

1. A method of treating Chronic Lung Disease comprising administering toa subject in need of treatment insulin-like growth factor-1 (IGF-1) oran agonist or an analog thereof.
 2. The method of claim 1, wherein theIGF-I or agonist or analog thereof comprises IGF-1 and an IGF bindingprotein.
 3. The method of claim 2, wherein the IGF-I or agonist oranalog thereof comprises IGF-1 and insulin-like growth factor bindingprotein-3 (IGFBP-3).
 4. The method of any one of the preceding claimsclaim 1, wherein the subject in need of treatment is an infant. 5-6.(canceled)
 7. The method of claim 1, wherein the IGF-I or agonist oranalog thereof is administered subcutaneously, intravenously,intramuscularly, or orally.
 8. (canceled)
 9. The method of claim 1,wherein the IGF-I or agonist or analog thereof is administered at adosage of about 100 to 500 micrograms/kg/24 hours. 10-11. (canceled) 12.The method of claim 1, wherein the IGF-I or agonist or analog thereof isadministered from the time of birth up to post-menstrual age (PMA) ofabout 24-34 weeks.
 13. The method of claim 1, wherein the IGF-I oragonist or analog thereof is administered from the time of birth up toPMA of about 28 to 32 weeks.
 14. The method of claim 1, wherein theIGF-I or agonist or analog thereof is administered from the time ofbirth up to PMA of about 29 weeks plus 6 days.
 15. The method of claim1, wherein the subject has reduced IGF-1 serum levels.
 16. The method ofclaim 15, wherein the reduced IGF-1 serum levels are about 30 to 50micrograms/L.
 17. The method of claim 1, wherein the IGF -1 isrecombinantly produced.
 18. The method of claim 3, wherein the IGFB P-3is recombinantly produced.
 19. The method of claim 3, wherein the IGF-1and the IGFBP-3 are complexed prior to administration to the subject.20. The method of claim 3, wherein the IGF-1 and IGFBP-3 are complexedin equimolar amounts.
 21. The method of claim 1, wherein theadministration of the IGF-I or agonist or analog thereof results inreduced incidence of Chronic Respiratory Morbidity (CRM) through 12months corrected age (CA).
 22. The method of claim 1, wherein theadministration of the IGF-I or agonist or analog thereof results inreduced incidence of Bronchopulmonary dysplasia (BPD) throughpostmenstrual age (PMA) 36 weeks, 40 weeks, 6 months, 8 months, 10months, or 12 months.
 23. The method of claim 1, wherein theadministration of the IGF-I or agonist or analog thereof results inreduced incidence of Severe Intraventricular Hemorrhage (IVH) Grade IIIor IV through postmenstrual age (PMA) 36 weeks, 40 weeks, 6 months, 8months, 10 months, or 12 months.
 24. The method of claim 1, wherein theadministration of the IGF-I or agonist or analog thereof results inreduced incidence of retinopathy of prematurity (ROP) throughpostmenstrual age (PMA) 36 weeks, 40 weeks, 6 months, 8 months, 10months, or 12 months.
 25. The method of claim 1, wherein theadministration of the IGF-I or agonist or analog thereof results inincreased Functional Status as Assessed by PREMature Infant Index(PREMII) through postmenstrual age (PMA) 36 weeks, 40 weeks, 6 months, 8months, 10 months, or 12 months.